The objectives of the proposed research are to elucidate the mechanisms of macromolecular transport through the arterial endothelium and subendothelial wall and to study the influences of hemodynamic factors, high lipid diet and endothelial turnover on these transport processes. This interdisciplinary project represents a coordinated program of theoretical and experimental investigations. In the proposed theoretical work, new models will be developed to study transport through an intact and leaky endothelium and the arterial wall. Transport through intercellular clefts will be analyzed in terms of the size and charge of the macromolecules and the geometry of the intercellular cleft, which in turn will be modeled as a function of transmural pressure and filtration flow. Transport in the arterial wall in the presence of leaky endothelial junctions or endothelial injuries will be studied in time-dependent and steady state models. Time-dependent filtration and consolidation in the artery wall will be analyzed under normotensive and hypertensive states. Experimental studies will be performed in parallel with the theoretical investigations to test the validity of the models and to provide data for the improvement of the theories. The experiments are designed to study macromolecular transport in the arterial endothelium, including intercellular clefts and vesicles, the subendothelial wall and the vasa vasorum, especially in terms of (a) the basic mechanisms of transport, (b) the effects of endothelial cell turnover and injury, and (c) the influence of hemodynamic factors and high lipid diet. Most of the experiments will be performed on the rabbit and studies will also be done on pigs (high lipid diet) and rats (spontaneously hypertensive). A variety of macromolecular tracers will be studied, including colloidal gold and 3H-dextran of various sizes, cationized and anionized ferritins, and low density lipoproteins labeled by different techniques (125I-LDL, fluorescent LDL, and Au-LDL). Functional data on transport will be obtained by radioactivity assay, fluorescence microscopy and electron microscopy, and correlated with the ultrastructural findings on the arterial wall. The results of the coordinated theoretical and experimental investigations on macromolecular transport should improve our understanding of atherosclerosis.